IL-11 signaling as a therapeutic target for cancer.

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IL-11 signaling as a therapeutic target for cancer

IL-11 is a member of the IL-6 family of cytokines. While it was discovered over 20 years ago, we have very little understanding of the role of IL-11 during normal homeostasis and disease. Recently, IL-11 has gained interest for its newly recognized role in the pathogenesis of diseases that are attributed to deregulated mucosal homeostasis, including gastrointestinal cancers. IL-11 can increase the tumorigenic capacity of cells, including survival of the cell or origin, proliferation of cancerous cells and survival of metastatic cells at distant organs. Here we outline our current understanding of IL-11 biology and recent advances in our understanding of its role in cancer. We advocate that inhibition of IL-11 signaling may represent an emerging therapeutic opportunity for numerous cancers. Keywords: cancer • GP130 • IL-11 • IL-6 • inflammation • STAT3 • therapy

Background IL-11 is a member of the IL-6 family of cytokines, which includes IL-6, LIF, OSM, CNTF, CT-1, CLC, IL-27 and IL-31. IL-6, the family namesake, is by far the most extensively characterized cytokine of this family, despite the shared use of a common receptor subunit, GP130, among the cytokines of this family. Recently, a renewed focus on understanding the biological activities of these cytokines has revealed unique roles for individual IL-6 cytokine family members [1–4] . Most notably, differences have been revealed between IL-11 and IL-6, which are the only cytokines that utilize GP130 in a homo dimeric complex (Figure 1), with IL-11 having unique roles during the onset and progression of various solid cancers. Here we provide an overview of our understanding of the biology of IL-11 signaling, highlighting the emerging role of IL-11 in cancer development. Discovery & source of IL-11 IL-11 was originally discovered as a soluble factor, present in the supernatants recovered from transformed PU-34 stromal cells, which when applied to T1165 plasmacytoma

10.2217/IMT.15.17 © 2015 Future Medicine Ltd

Tracy L Putoczki1 & Matthias Ernst*,1,2 The Walter & Eliza Hall Institute of Medical Research & Department of Medical Biology, University of Melbourne, Parkville Victoria 3052, Australia 2 Current address: Olivia Newton-John Cancer Research Institute & School of Cancer Medicine La Trobe University, Heidelberg Victoria 3084, Australia *Author for correspondence: Tel.: +61 3 9496 9775 Fax: +61 3 9496 5334 matthias.ernst@ onjcri.org.au 1

cells stimulated their proliferation [5] . IL-11 was subsequently molecularly cloned from a cDNA library, that was generated from the PU-34 cell line, and predicted to encode a mature secreted protein of 178 amino acids with a molecular mass of approximately 19 kDa [5] . The corresponding genomic sequence encompasses 7 kb and comprises 5 coding exons located on chromosome 19q13.3–19q13.4 [6] . The crystal structure of human IL-11 reveals a typical type-1 four helix monomeric bundle, with structural features that are distinct from other IL-6 family cytokine members [7] . Despite its discovery over 20 years ago, little is known about the source and regulation of IL-11 expression in vivo. The 5′ region of the IL-11 gene contains numerous cis-regulatory elements, including two AP-1 motifs that are essential for TGF-β1induced IL-11 transcriptional activation, in addition to binding sites for SP-1, STAT3, STAT5a, CTF/NF-1 and IFN/1 as well as a putative NFκB binding element [5,8] . Recently, post-transcriptional regulation of IL-11 has been identified following TGFβ-dependent induction of the long noncod-

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GP130-GP130 IL-6

CNTF

CLC

OSMR-GP130/other CT-1

OSM

OSM

WSX-GP130

IL-31

IL-27

GP130

WSX

IL-31R

OSMR

GP130

OSMR

GP130

LIFR

GP130

LIFR

GP130

LIFR

CNTFR

LIFR

LIFR

CNTFR GP130

Intracellular

GP130

GP130

IL-11R

GP130

IL-11R

IL-6R

GP130

Cell membrane

LIF

p28 EBI3

GP130 IL-6R

Extracellular

LIFR-GP130

IL-11

Figure 1. The IL-6 family of cytokines. Members of the IL-6 family of cytokines are generally defined by their shared use of the transmembrane GP130 β-subunit receptor. IL-6 and IL-11 are unique, in that they are the only family members to utilize GP130 as a homodimeric complex.

ing RNA, IncRNA-ATB, interacting with IL-11 mRNA and increasing its stability [9] . Low levels of IL-11 mRNA can be detected in the murine thymus, spleen, bone, heart, lung, GI tract, kidney, brain, spinal cord, testis, uterus and ovaries [10,11] . We now appreciate that IL-11 is produced by many different types of cells within these organs in response to a variety of stimuli, including cytokines and respiratory viruses (Table 1). Subepithelial myofibroblasts are believed to be the most abundant cellular source of IL-11 and produce IL-11 in response to TGF-β, IL-1β or IL-22 [12,13] . However, gastrointestinal epithelial cells are also a major source of secreted IL-11 [14] . In bronchial epithelial cells IL-17F, IL-1β, TGF-β and retinoic acid (RA) induce IL-11 secretion [15,16] , while in retinal pigment epithelial cells IFN-γ can induce IL-11 secretion [17] . Other studies suggest that during a wound healing response, COX-2 induces IL-11 expression in epithelial cells [18] and TNF-α induces IL-11 expression in colonic smooth muscle cells [19] . These observations suggest a highly complex interplay between IL-11 and other cytokines within epithelial microenvironments. Extracellular IL-11 signaling interactions A unique feature of the IL-6 cytokine family is their shared interaction with the transmembrane glyco protein β-receptor subunit, GP130 (also known as IL6ST or CD130; Figure 1). Since GP130 is ubiquitously expressed, with the exception of pre-B-cells, the ability of cells to respond to a particular IL-6 family cytokine is determined by the expression of α-receptor subunits. IL-11 initiates signaling following binding to a unique IL-11Rα, while other members of this family utilize their own specific low affinity subunits including for example, IL-6Rα, CNTFR, LIFR (also known as CD118), OsMR and WSX-1 (also known as IL-27R or TCCR). Comparison of the amino acid sequences suggests that IL-11Rα is most closely related to the IL-6Rα subunit (24% amino acid homology) and the CNTF α-receptor (22% amino acid homology). The formation of an IL-11/IL-11Rα complex allows for a high-affinity interaction with GP130 potentially as a tetrameric com-

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plex [30] , and the subsequent formation of a hexameric complex in a 2:2:2 formation (IL-11/IL-11Rα/GP130), for which only a low resolution cryo-electron micrograph 30 Å structure is available [31] . The 10 kb human IL-11Rα gene contains 13 exons and maps to chromosome 9p13 [32] . Murine IL-11Rα1 is composed of 14 exons, with an alternative IL-11Rα2 locus sharing 99% exon coding sequence identity with IL-11Rα1, but differing in the 5′ untranslated region. There are two isoforms of human IL-11Rα, which differ in the structure of their cytoplasmic domains [33] , but share 84% overall amino acid homology to murine IL-11Rα. The first isoform is most similar to mouse IL-11Rα and human IL-6Rα, with a short cytoplasmic domain, while the second isoform lacks the cytoplasmic domain. Proof-of-principle studies utilizing recombinant IL-11Rα protein that lacked the cytoplasmic domain demonstrated that a soluble (s) IL-11/IL-11Rα complex is capable of ‘trans-signaling’ in vitro, in a manner akin to the sIL-6/IL-6Rα complex [34] . The potential capacity of IL-11 to act on cells by trans-signaling in vivo would increase the spectrum of IL-11 responsive cells, as any cell expressing GP130 could respond to the IL-11/IL-11Rα complex. Although transcripts that could give rise to a soluble form of IL-11Rα have been identified, to date a soluble form of the protein has not been observed in vivo [35] . The factors that contribute to the regulation of IL-11Rα expression are not clear. The human IL-11Rα gene contains putative p53 and AP-1 binding motifs. In mice, IL-11Rα1 is expressed in the brain, bone, spleen, thymus, bladder, heart, lung, kidney, muscle, salivary glands, GI tract, uterus, ovaries, testis and a number of primary cell types such as macrophages, T-cells, osteoblasts and osteoclasts (Table 2) [10,36,37] . While expression of IL-11Rα2 is restricted to the testis, lymph nodes and thymus [38] . IL-11 mediated intracellular signaling pathways In response to ligand-dependent formation of the GP130-containing receptor complexes, juxta-position-

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Table 1. Tissues and organs that produce IL-11. Tissue/organ

Cell type

Stimulators

Ref.

Bone/connective tissue

Articular chondrocytes

TGF-β, IL-1β

[20]

Synoviocytes

TGF-β, IL-1β

[20]

Osteoblasts

TGF-β, SMAD1

[21]

CNS

Neurons

IL-1α

[11]

Endometrium/uterus

Epithelial cells

Endogenous

[22]

[23]

Stromal cells Liver

Hepatocytes

Oxidative stress

Lung

Eosinophils

Viruses, TGF-β, IL-1β

Epithelial cells

IL-13, IL-17F, IL-1β, TGF-β, RA

Fibroblasts

TGF-β, IL-1β, histamine

Macrophages

Viruses

[28]

Gastrointestinal tract

Epithelial cells

COX-2

[18]

Smooth muscle cells

TNF-α

[19]

Myofibroblasts

TGF-β, IL-1β or IL-22

Skin

Dermal fibroblasts

TGF-β, IL-1β

ing of the associated Janus kinases (JAKs) results in their activation, through trans-phosphorylation, which facilitates the transfer of phosphate (p) groups to several intracellular tyrosine (Y) residues in the cytoplasmic tail of GP130 [6] . In turn, this initiates distinct intracellular signaling cascades by creating docking sites for SH2 domain-containing signaling proteins (Figure 2) . Specifically, the four membrane distal pY residues in GP130, which conform to a pYxxQ motif where x is any amino acid followed by glutamine (Q), provide docking sites for the latent transcription factors STAT1 and STAT3 [53] . This enables phosphorylation of a conserved Y residue in the carboxyl-terminal portion of these STAT proteins, allowing for the formation of homo- or heterodimers, which, upon active transport into the nucleus, bind to DNA in a sequence specific manner to regulate gene transcription [15] . Additional phosphorylation of STAT1 and STAT3 on C-terminal serine (S) residues may increase their transcriptional activity, while selectively pS-modified STAT3 has been proposed to functionally link STAT3 to the mitochondrial electron transport chain [54] . Among the transcriptional target genes for STAT3, SOCS3 is an important negative regulator of GP130 signaling by limiting the duration, but not amplitude, of the receptor signal. To achieve this, SOCS3 binds through its SH2-domain to the membrane-proximal pYxxV motif of GP130, and interacts simultaneously through its N-terminal motif with a JAK molecule to occlude access to the substrate binding pocket of JAKs [55] . The same membrane-proximal pYxxV residue also provides a docking site for the Y-phosphatase


[24] [15,16,25] [26,27]

[12,13] [29]

SHP2, which provides the architectural framework for GP130-dependent activation of the RAS/ERK signaling cascade. IL-11 has also been shown to activate both p42 and p44 MAPK in HUVEC endothelial cells, K562 cells, monocytic leukemia U936 cells and 3T3-L1 adipocytes [17,56] . IL-11-dependent engagement of the PI3K/AKT/mTOR pathway independent of pY-GP130 can also occur, indicated by increased phospho-S6 ribosomal protein, but does require JAK activation [57] . Role of IL-11 in disease The physiological role of IL-11 signaling has been functionally characterized through the analysis of il-11rα1KO mice. Under standard conditions, the only major phenotype in these mice is the failure of females to support embryonic development past day 5 of pregnancy, which is associated with defective decidua formation [58] . This suggests that other cytokines that engage GP130 are able to maintain global tissue homeostasis in the absence of IL-11 signaling. However, we and others have recently found essential roles for IL-11 signaling at mucosal surfaces during specific disease states [14,39,59] . Hematopoietic & immune activities

The most well recognized role for IL-11 is in megakaryocytopoiesis in vitro and in vivo, where it increases the frequency and proportion of proliferating megakaryocytes in the bone marrow [39,40] . Despite megakaryocytes expressing IL-11Rα, and not platelets, when recombinant (r) IL-11 is administered to mouse,

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Table 2. Tissues and organs that respond to IL-11 signaling. Tissue

Cell type

Response

Bone marrow

Megakaryocytes

Increase platelet numbers

Bone

Osteoblasts

Increase bone resorption

[36]

Osteoclasts

Osteoclast development

Breast

Macrophages

Decrease IL-12, increase IkB-α/β

[41]

Epithelial cells

Undergo EMT

[41]

CNS

Oligodendrocytes

Enhanced numbers

Endometrium

Epithelial cells

Increase TNF-α

[44]

Endothelial cells

N/A

[45]

Smooth muscle

N/A

[45]

Kidney

Tubule cells

Increase HIF1-α

[46]

Liver

Hepatocytes

Production of acute phase proteins and TIMP-1

[23]

Macrophages

Reduce Th1 cytokines

[47]

Lung

Epithelial cells

Induce fibrosis

[24]

Macrophages

Decrease TNF-α, IL-1β, IL-12

T cell and NK cells

Decrease IFN-γ

[47]

Gastrointestinal tract

Epithelial cells

Mucosal recovery

[48]

Stem cells

Survival

[49]

Skin

T cells

Alleviate psoriasis

[50]

Spleen

T cells

Cachexia

rat, dog, hamster and primates a 30–50% elevation in platelet numbers is observed, highlighting an important role for IL-11 in the stimulation of platelet production by mature megakaryocytes [40,60] . Based on these observations, numerous clinical trials in patients with breast cancer were conducted and showed that treatment of patients with rIL-11 before chemotherapy increased platelet levels, and after chemotherapy reduced the need for bone marrow transplants [61,62] . Ongoing clinical studies in patients with myeloid malignancies, including leukemia, are investigating the potential for rIL-11 to reduce the severity of thrombocytopenia and infection in patients undergoing chemotherapy treatments [63,64] . In bone marrow failure syndromes, including aplastic anemia and myelodysplastic syndrome, clinical trials are underway to determine if rIL-11 can raise platelet counts [65,66] . Recently, a modified form of rIL-11 has been developed that is effective at reducing chemotherapy-induced thrombocytopenia at lower doses [67] . Together, these studies have demonstrated the utility of rIL-11 as an agent to reduce severe chemo therapy-induced thrombocytopenia, resulting in the FDA approval and routine clinical use of Oprelvekin, also marketed under the trade name Neumega [68,69] . IL-11 has also been shown to stimulate erythropoiesis and regulate macrophage proliferation and

444

Ref. [39,40]


[42,43]

[37,47]

[50–52]

differentiation [70] . Macrophages express IL-11Rα, which facilitates a reduction in intra-cellular pro inflammatory cytokine production including TNFα, IL-1β, IL-12p40 and IL-6, which in turn increases the expression of IκB resulting in the inhibition of NFκB nuclear translocation [37,71] . IL-11 also restricts T-helper differentiation by modulating Th1/Th2 cytokine production from activated CD4 + T-cells, resulting in production of IL-4 and IL-19, and inhibition of IL-12 and IFN-γ, which has been associated with a decrease in inflammatory tissue damage [50,51] . IL-11 has also been shown to play a role in the differentiation of NK cells, particularly at the maternal–fetal interface [72] . In contrast, IL-11 does not appear to effect the function of neutrophils [73] . In bone marrow stromal cells and osteoblasts, RankL induces IL-11 expression in BMSC and endothelial cells [74] . IL-11 can in turn activate endothelial cells to resist lysis by allospecific class I MHC-restricted cytolytic T-lymphocytes, suggesting that IL-11 contributes to resistance from immune-mediated injury [56] . Mucosal & cell injury

In the late 1990s, there was a flurry of activity around the potential for rIL-11 to ameliorate intestinal damage. This was driven by observations in rat and mouse



Cancer onset & progression

Elevated IL-11 expression has recently been reported in various human cancers of both hematopoietic and of epithelial origin (Table 3) . IL-11 is produced directly by melanoma, breast, colon and non-small-cell lung cancer cells [95–97] . In a mouse mammary tumor model, IL-11 is produced not only by the cancer cells, but also by the tumor infiltrating macrophages and T-lymphocytes [41] , while cancer-associated fibroblasts appear to be the primary source of IL-11 in human colorectal cancer biopsies [98] . Elevated IL-11 expression levels are


Cell membrane Intracellular

JAKs

GP130

Extracellular

IL-11R

IL-11

GP130 IL-11R

models of ulcerative colitis and Crohn’s disease, where rIL-11 alleviated clinical features of inflammation and reduced intestinal damage [39,59,75–77] . Since then, sequence polymorphisms in the human IL-11 gene have been linked to ulcerative coltiis [78] . In line with these observations, rIL-11 was shown in mice to protect small intestinal cells from bowel injury associated with graft-versus-host disease, lethal gamma and neutron body irradiation, chemotherapy damage and ischemia [39,51,76,79–81] . In all of these models, rIL-11 treatment minimized mucosal damage, increased the wound-healing response and improved overall survival. These observations were extended to models of Gram-negative sepsis, toxic shock, anoikis radiation and ischemia-reperfusion injury, where rIL-11 was shown to suppress apoptotic cell death and simultaneously promote proliferation of the intestinal epithelium [82–85] . As a result of these observations rIL-11 entered clinical trials for mucositis [86] and Crohn’s disease, and appeared to be well-tolerated and achieved disease remission in a subset of patients [87–89] . These prosurvival effects are not limited to the intestine, IL-11 also acts directly on hepatocytes to induce the production of acute-phase proteins and to reduce hepatocyte necrosis and apoptosis [23,90] . As a result of these studies, rIL-11 has undergone clinical trials in patients with Hepatitis C and advanced liver disease [91] . IL-11 is also likely to regulate lung morphology. In humans, IL-11 gene polymorphisms have been linked to chronic obstructive pulmonary disease [92] . In mice, the provision of rIL-11 decreased hyperoxic lung injury and improved survival after thoracic irradiation [93,94] . However, sustained IL-11 expression has also been reported to induce airway remodeling and subepithelial fibrosis [24] . While the protective mechanisms of IL-11 in models of mucosal damage are not entirely clear, it appears that IL-11 has evolved to mediate effective wound healing responses, which is likely attributed to the expression of IL-11 by cells of the mesenchymal lineage, including fibroblasts, BMSC, placental stromal cells, articular chondrocytes and synoviocytes (Table 1) [20] .

Review

SHP2

SOCS3

P

P STAT3

PI3K

RAS

P

P STAT1

Akt

MEK

mTOR

Erk

Figure 2. The IL-11 signaling pathway. Formation of an IL-11 signaling complex results in the recruitment of JAKs, which permit the phosphorylation of STAT proteins and activation of the PI3K pathway. At the same time, SHP2 interaction with GP130 allows for activation of the RAS/Erk signaling pathway.

linked to poor prognosis in human cancers, for example in endometrial and gastric adenocarcinomas the expression of IL-11 increases with tumor grade [99,100] , while in breast cancer the level of IL-11 can predict the development of metastatic spread to bone [101,102] . While we now appreciate that IL-11 is present in numerous types of cancer, we have very little understanding of the role of IL-11 within these tumors. The expression of IL-11Rα and GP130 on the cells that drive tumor progression provides the scaffolding required for the activation of STAT3 and Ras/ERK signaling pathways. Many cancer cells grow in a hypoxic environment, with hypoxia-associated accumulation of HIF-1 and AP-1 resulting in transcriptional activation of the IL-11 promoter, which has been linked to the survival of cancer cells [115] . In colon cancer cells, IL-11 has been shown to activate ERK1/2 signaling resulting in increased proliferation [120] , while IL-11 has been shown to increase the invasiveness of both gastric and colon cancer cells [105,120,121] . Numerous breast and prostate cancer xenograft experiments have demonstrated tumor promoting activities of IL-11 [79] , with recent reports highlighting that IL-11 functions in a non-cell-autonomous manner in a subpopulation of clonal breast cancer cells to promote the survival of all tumor cells [122] . This subclonal population of cells overcomes constraints put in place by the micro environment, which does not require additional stochasitc events [122] . For example, IL-11 driven tumors had a higher vasculature density and reorganization of the extracellular matrix [122] . The major limitation of these xenograft studies is the lack of the complex interactions that occur between cancer and stromal cells within the tumor micro


445


Table 3. Cancers associated with increased IL-11 signaling. Cancer

Human observation

Mouse observation

Ref.

Bone

Cell lines express and primary tumors express IL-11

Required for orthotopic models

Breast

Cell lines and primary tumors express IL-11

Required for primary tumor growth and metastasis

[101]

Colorectal

Cell lines and primary tumors express IL-11 Elevated IL-11 is linked to poor prognosis


[98,105]

Endometrial

Elevated in primary tumor and increased with grade

N/A

Glioblastoma

Cell lines express IL-11

N/A

[106]

Liver

Elevated in primary tumor, linked to bone metastasis

N/A

[107,108]

Leukemia

Elevated IL-11 and IL-11Rα

N/A

[109]

Lung

Elevated IL-11

N/A

[110]

Hodgkin’s lymphoma

Presence of IL-11Rα

N/A

[111]

[103,104]

[45,99]

Ovarian

Presence of IL-11Rα

N/A

Pancreatic

Elevated in primary tumors

Elevated in advanced tumor

[113,114]

Prostate

Elevation associated with progression

Increase human cell line xenograft growth

[115–117]

Renal


N/A

[118]

Skin


N/A

[119]

Stomach

Cell lines and primary tumors express IL-11 Elevated IL-11 is linked to poor prognosis


environment. However, the emerging use of models of endogenous tumor formation in fully immune-competent mice has recently provided us with significant insight into the role of IL-11 in cancer progression. In mouse models of colitis-associated cancer and sporadic colon cancer, respectively, IL-11 is elevated in tumor tissue [105] , with production of IL-11 by myeloid cells linked to metastasis [123] . Although the molecular trigger for elevated IL-11 expression remains elusive, a recent study suggests that dietary iron increases colonic inflammation and the production of IL-11, which in turn promotes colonic tumor development [124] . Other studies implicate deregulated innate immune responses associated with loss of the inflammation-associated signaling node, Myd88 to the exacerbated expression of IL-11 [125] . In order to define the requirement of IL-11 signaling for tumor progression, we recently exploited the il-11rα1KO mice, which are unable to respond to IL-11. In these studies, we conclusively demonstrated that IL-11 signaling is essential for tumor onset and progression, since mice lacking IL-11Rα developed very few tumors in colitis-associated cancer and sporadic colon cancer models [105] . Our studies further highlight that the nonhemopoietic, rather than hemopoietic compartment responded to IL-11 to promote tumor formation. In turn, the genetic loss of IL-11Rα resulted in a reduction in STAT3 activation and tumor

446


[112]

[100,105]

cell proliferation [105] . Similarly, in a gastric cancer mouse model that is dependent on STAT3 activation for tumor progression, we have demonstrated that even partial genetic inhibition of IL-11 signaling resulted in a significant decrease in tumor burden [8,105] . Together, these findings strongly suggest that IL-11 signaling promotes the progression of gastrointestinal cancers. In order to begin to understand the complex mechanisms behind the role of IL-11 in tumor progression, it will be essential to build on our knowledge of the role of IL-11 in normal development. For example, IL-11 and IL-11Rα are expressed by vascular endothelial smooth muscle cells in the first trimester of pregnancy, suggesting a role for IL-11 signaling during remodeling of the vasculature [126] . This observation is consistent with the proangiogenic role of IL-11 in lung cancer [127] . Similarly, IL-11 regulates the adhesive properties of endometrial luminal epithelium [128] , a feature likely to be exploited by tumor cells for their clonal expansion. Taking advantage of our current knowledge will allow us to build a conceptual framework that allows us to differentiate between the roles of IL-11 in tissue homeostasis, primary tumor formation and the metastatic spread of tumor cells. Metastasis

The requirement of IL-11 for bone formation was one of the first activities attributed to IL-11 outside of the



hemopoietic system. Interestingly, this function was based on the observation that the osteolytic metastases of human breast cancer cells were linked to the production of IL-11 by bone forming osteoblasts [129] . Subsequent findings suggested that primary osteoblasts constitutively express IL-11 and IL-11Rα, which collectively creates a prosurvival niche for metastatic cells [36] . Other reports suggest that melanoma cells induce IL-11 production by bone derived endothelial cells [130] . Although IL-11 promotes effective osteoclast differentiation, and therefore bone resorption, it is now clear that the osteolytic activity of most cancer cells also depends on their capacity to produce PTHrP, RANKL and other osteolytic factors. Accordingly, il-11rαdeficient mice have reduced osteoclast numbers [131] , consistent with the observation that PTH-stimulated osteoclast formation also requires IL-11 signaling [132] . Incidentally, IL-11 and PTHrP are classical TGF-β response genes with many examples confirming that cancer cell-derived TGF-β, a prometastatic cytokine, stimulates the production of IL-11 in many different stromal cell types (Table 1) . Accordingly, ablation of the TGF-β-signaling node SMAD4 in breast cancer cells has been shown to attenuate the capacity of these cells to produce IL-11 and to metastasize to bone [133] . Likewise, overexpression of the cytosolic TGF-β signaling antagonist SMAD7 in melanoma cells reduced IL-11 expression and osteolytic lesions [134] . In colon cancer, TGF-β has been shown to increase the production of IL-11 by cancer-associated fibroblasts in the tumor microenvironment, which enables the survival and proliferation of IL-11Rα expressing colon cancer cells at metastatic sites [98] . This observation may be augmented by TGF-β-dependent induction of a long noncoding RNA that simultaneously facilitates expression of the epithelial-to-mesenchymal (EMT) regulators ZEB1/2, which are associated with cancer cell invasion, as well as promoting IL-11 mRNA stability and downstream activation of STAT3, which enables cancer cells to colonize distant organs [9] . EMT often correlates with therapy resistance, and recently it has been suggested that miRNA-30c, a prognostic marker for breast cancers, promotes EMT by binding to the actin-binding protein TWINFILIN 1, which then targets the production of IL-11. Accordingly, high IL-11 expression is inversely correlated with miRNA-30c as well as miRNA-204, miRNA-211 and miR-379 expression, and this was associated with reduced survival in breast cancer patients [135,136] . Therapeutic inhibition of IL-11 signaling Given the recent identification of the protumorigenic activities elicited by IL-11, it is not surprising that a new focus has been placed on generating therapeutic


Review

reagents that will inhibit this signaling pathway. The clinical success of anticytokine and anticytokine receptor antibodies in treating inflammatory diseases, for example, infliximab (anti-TNF-α) and tocilizumab (anti-IL-6R), have paved the way for the development of other targeted cytokine signaling inhibitors, including sgp130Fc binding protein (inhibiting IL-6/sIL-6R), which has passed a Phase I clinical trial. In this context, a number of approaches to inhibit of IL-11 signaling are feasible, including targeting the IL-11 ligand itself, or components of the receptor signaling complex including IL-11Rα, GP130 or downstream JAKs. Antibodies that inhibit signaling by mouse IL-11 [28] , IL-11Rα [Putoczki TL, Unpublished Data] or GP130 have been developed, and show promise in modulating disease in numerous mouse models. The demonstration that the genetic loss of IL-11Rα or the therapeutic administration of IL-11 Mutein, an IL-11 signaling antagonist, inhibits tumor growth in mice and provides the rationale for generating and benchmarking the efficacy of the equivalent human reagents [14] . With this in mind, antibodies that inhibit human IL-11 (R&D), IL-11Rα [Putoczki TL, Unpublished Data] or GP130 [137] are currently in preclinical development. Targeting of IL-11 or IL-11Rα is the most direct approach to inhibiting this signaling pathway, since targeting GP130 could lead to the inhibition of other IL-6 family cytokines. This may lead to unwanted side effects, which is best highlighted by the observation that gp130KO mice are embryonic lethal. However, neutralizing GP130 antibodies have been developed that specifically inhibit IL-11 signaling [138] . Indeed neutralizing human IL-11 and IL-11Rα [Putoczki TL, Unpublished Data] antibodies have shown promise in xenograft models. In addition, binding proteins, including IL-11 Mutein, that inhibit both mouse and human IL-11 signaling have been developed, and are effective in treating gastric, colon and breast cancer xenografts [105] . There is precedent for the clinical use of engineered binding proteins, with anakinra (IL-1R antagonist) widely used to treat a number of diseases. Finally, expression of chimeric antigen-receptor strategies that are based on IL-11Rα expression have recently been exploited to mediate cytotoxic T-cell killing of human osteosarcoma cells [139] . In mouse models, no adverse side effects, including alteration of platelet counts, have been observed following the long-term therapeutic inhibition of IL-11 signaling [105] . This is in line with the observation that the number of hemopoietic progenitor cells, as well as their terminally differentiated progeny are undisturbed in il-11rα1KO mice [140] . It remains to be determined if these observations will remain true for humans treated with IL-11 signaling inhibitors, with clinical observations


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Review Putoczki & Ernst with JAK inhibitors often associated with numerous side effects, including thrombocytopenia [141] .

single therapy, or in combination with current standard of care therapies.

Conclusion & future perspective For the past 20 years, rIL-11 has been under intense investigation for its therapeutic potential to minimize hematopoietic and gastrointestinal toxicity associated with radiological and nuclear cancer treatments. These efforts were underpinned by the prosurvival properties that rIL-11 imparted on hematopietic and gastro intestinal cells. However, work by our laboratories and others place a new perspective on the use of rIL-11 in cancer patients, given that IL-11 has clear protumorigenic and prometastatic roles in mouse and human xenograft models. As our understanding of the role of IL-11 during cancer progression and other normal physiological states evolves, we will learn more about the molecular make-up of cancer subtypes and patient subpopulations that will most likely benefit from IL-11 signaling inhibition as a

Financial & competing interests disclosure The work in the laboratory of M Ernst is supported by the Ludwig Institute for Cancer Research. The work in the laboratories of M Ernst and TL Putoczki is supported by the Victorian State Government Operational Infrastructure Support, and NHMRC grants 1008614 and 1080498 (to TL Putoczki) and 603122, 1064987, 1069024 and 1079257 (to M Ernst) and WCRF, formally AICR (to TL Putoczki). Both authors are inventors of patents describing the use of IL-11 antagonists for the treatment of cancer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Executive summary Discovery & source of IL-11 • IL-11 was discovered over 20 years ago. • The predominant sources of IL-11 are leukocyte, fibroblast and epithelial cells.

Extracellular IL-11 signaling interactions • IL-11 interacts with a cell-type specific α-subunit receptor (IL-11Rα). • IL-11/IL-11Rα interact with GP130 in a 2:2:2 hexameric configuration. • The expression of IL-11Rα is limited to specific cell populations. • GP130 is ubiquitously expressed.

IL-11 mediated intracellular signaling pathways • IL-11 activates Janus kinase/STAT3, ERK/RAS and mTor/PI3K signaling pathways.

Role of IL-11 in disease • IL-11 has roles in hematopoietic and mucosal biology. • IL-11 expression is elevated in numerous human cancers. • Animal models have provided significant insight into the importance of IL-11 to cancer progression. • IL-11 drives metastasis in mouse models.

Therapeutic inhibition of IL-11 signaling • Inhibition of IL-11 signaling alleviated cancer in mouse and human xenograft models. • Clinically relevant inhibitors of IL-11 signaling are now in development.

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